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Structural and kinetic analysis of protein-aggregate strains in vivo using binary epitope mapping
Umeå University, Faculty of Medicine, Department of Medical Biosciences.
Umeå University, Faculty of Medicine, Department of Medical Biosciences.
Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
Umeå University, Faculty of Medicine, Department of Medical Biosciences.
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2015 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 112, no 14, 4489-4494 p.Article in journal (Refereed) Published
Abstract [en]

Despite considerable progress in uncovering the molecular details of protein aggregation in vitro, the cause and mechanism of protein-aggregation disease remain poorly understood. One reason is that the amount of pathological aggregates in neural tissue is exceedingly low, precluding examination by conventional approaches. We present here a method for determination of the structure and quantity of aggregates in small tissue samples, circumventing the above problem. The method is based on binary epitope mapping using anti-peptide antibodies. We assessed the usefulness and versatility of the method in mice modeling the neurodegenerative disease amyotrophic lateral sclerosis, which accumulate intracellular aggregates of superoxide dismutase-1. Two strains of aggregates were identified with different structural architectures, molecular properties, and growth kinetics. Both were different from superoxide dismutase-1 aggregates generated in vitro under a variety of conditions. The strains, which seem kinetically under fragmentation control, are associated with different disease progressions, complying with and adding detail to the growing evidence that seeding, infectivity, and strain dependence are unifying principles of neurodegenerative disease.

Place, publisher, year, edition, pages
National Academy of Sciences , 2015. Vol. 112, no 14, 4489-4494 p.
Keyword [en]
protein aggregation, neurodegeneration, strain, amyotrophic lateral sclerosis, transgenic mice
National Category
Pharmacology and Toxicology Medical Bioscience
Identifiers
URN: urn:nbn:se:umu:diva-103147DOI: 10.1073/pnas.1419228112ISI: 000352287800075PubMedID: 25802384OAI: oai:DiVA.org:umu-103147DiVA: diva2:814811
Available from: 2015-05-28 Created: 2015-05-18 Last updated: 2017-05-11Bibliographically approved

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Bergh, JohanZetterström, PerAndersen, Peter M.Brännström, ThomasGraffmo, Karin SixtensdotterJonsson, P. AndreasMarklund, Stefan
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Proceedings of the National Academy of Sciences of the United States of America
Pharmacology and ToxicologyMedical Bioscience

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